We have generated candidate vaccines against H9N2, H5N1, H7N3, H2N2, H6N1, H2N3, H7N7 and H7N9 influenza viruses. Based on promising preclinical data in mice and ferrets, clinical lots of these vaccines were generated for Phase I clinical trials of the safety and immunogenicity of the vaccines for healthy adults under an IND. The findings from the H9N2, H5N1, H7N3, H6N1 and H2N2 vaccine studies were included in previous reports. Antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) against avian influenza virus subtypes including H7N9 and H5N1 have been detected in human sera. There are limited data on the presence of such cross-reactive ADCC mediating antibodies (ADCC-Abs) in children and the viral target(s) of these Abs are poorly understood. Using high-throughput NK cell activation and NK cytotoxicity assays, we compared ADCC-Abs in sera collected from healthy infants (1 year), children (2-17 years) and adults (18 years) against H7N9 virus-infected cells and recombinant HA, NA and NP proteins. High titers of ADCC-Abs against H7N9 virus-infected cells were detected in sera from adults and children but not infants. Despite this, adult, children and infants had low or undetectable ADCC-Abs titers directed against H7N9 HA or NA proteins. Further analysis showed that ADCC-Abs titers were significantly higher towards H7N9 NP, as compared to H7N9 HA or NA proteins and correlated strongly with ADCC-Abs titers against H7N9 virus-infected cells. Indeed, ADCC-Abs to NPs of seasonal H1N1 and H3N2 viruses correlated strongly with ADCC-Abs to H7N9 NP, suggesting that seasonal influenza infections and vaccinations may induce these cross-reactive antibodies. Targeting ADCC-Abs to internal proteins may be a potential mechanism of universal vaccine design.